Apolipoprotein AI (ApoA-I) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''APOA1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
As the major component of
HDL particles, it has a specific role in
lipid metabolism.
Structure
''APOA1'' is located on
chromosome 11, with its specific location being 11q23-q24. The gene contains 4 exons.
The encoded apolipoprotein A-I, is a 28.1 kDa protein composed of 243 amino acids; 21 peptides have been observed through mass spectrometry data.
Function
Apolipoprotein AI is the major protein component of
high density lipoprotein (HDL) particles in
plasma
Plasma or plasm may refer to:
Science
* Plasma (physics), one of the four fundamental states of matter
* Plasma (mineral), a green translucent silica mineral
* Quark–gluon plasma, a state of matter in quantum chromodynamics
Biology
* Blood pla ...
.
Chylomicron
Chylomicrons (from the Greek χυλός, chylos, meaning ''juice'' (of plants or animals), and micron, meaning ''small particle''), also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85 ...
s secreted from the intestinal enterocyte also contain apo-AI, but it is quickly transferred to HDL in the bloodstream.
The protein, as a component of HDL particles, enables efflux of fat molecules by accepting fats from within cells (including macrophages within the walls of arteries which have become overloaded with ingested fats from oxidized LDL particles) for transport (in the water outside cells) elsewhere, including back to LDL particles or to the liver for excretion.
It is a cofactor for
lecithin—cholesterol acyltransferase (LCAT) which is responsible for the formation of most plasma
cholesteryl esters
300px, Cholesterol oleate, a member of the cholesteryl ester family
Cholesteryl ester, a dietary lipid, is an ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Chole ...
. Apolipoprotein AI has also been isolated as a
prostacyclin (PGI2) stabilizing factor, and thus may have an anticlotting effect. Defects in the gene encoding it are associated with HDL deficiencies, including
Tangier disease, and with systemic non-neuropathic
amyloidosis
Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight ...
.
ApoA-I is often used as a biomarker for prediction of cardiovascular diseases. The ratio apoB-100/apoA-I (i.e. LDL & larger particles vs. HDL particles), NMR measured lipoprotein (
low density lipoprotein
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density ...
(LDL)/(HDL) particle ratios even more so, has always had a stronger correlation with myocardial infarction event rates than older methods of measuring lipid transport in the water outside cells.
ApoA-I is routinely measured using immunoassays such as
ELISA
The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presence ...
or
nephelometry
A nephelometer or aerosol photometer is an instrument for measuring the concentration of suspended particulates in a liquid or gas colloid. A nephelometer measures suspended particulates by employing a light beam (source beam) and a light detec ...
.
Applications
ApoA-I can be used to create in vitro lipoprotein
nanodisc
A nanodisc is a synthetic model membrane system which assists in the study of membrane proteins. Nanodiscs are discoidal proteins in which a lipid bilayer is surrounded by molecules that are amphipathic molecules including proteins, peptides, and ...
s for cell-free membrane expression systems.
Clinical significance
Activity associated with high HDL-C and protection from heart disease
As a major component of the
high-density lipoprotein complex (protective "fat removal" particles), apoA-I helps to clear fats, including
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
, from white blood cells within artery walls, making the white blood cells (WBCs) less likely to become fat overloaded, transform into foam cells, die and contribute to progressive
atheroma. Five of nine men found to carry a mutation (E164X) who were at least 35 years of age had developed premature
coronary artery disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...
.
One of four mutants of apoA-I is present in roughly 0.3% of the Japanese population, but is found in 6% of those with low HDL cholesterol levels.
ApoA-I Milano is a naturally occurring mutant of apoA-I, found in a few families in
Limone sul Garda, Italy, and, by genetic + church record family tree detective work, traced to a single individual, Giovanni Pomarelli, in the 18th century. Described in 1980, it was the first known molecular abnormality of
apolipoproteins.
Paradoxically, carriers of this mutation have very low HDL-C (HDL-Cholesterol) levels, but no increase in the risk of heart disease, often living to age 100 or older. This unusual observation was what lead Italian investigators to track down what was going on and lead to the discovery of apoA-I Milano (the city, Milano, ~160 km away, in which the researcher's lab was located). Biochemically, apo A1 contains an extra
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
bridge, causing it to exist as a
homodimer or as a
heterodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
with apo A-II. However, the enhanced cardioprotective activity of this mutant (which likely depends on fat & cholesterol efflux) cannot easily be replicated by other cysteine mutants.
Recombinant ApoA-1 Milano dimers formulated into liposomes can reduce
atheromas in animal models by up to 30%. Apo A1 Milano has also been shown in small clinical trials to have a statistically significant effect in reducing (reversing) plaque build-up on arterial walls.
In human trials the reversal of plaque build-up was measured over the course of five weeks.
Novel haplotypes within apolipoprotein AI-CIII-AIV gene cluster
Lately, two novel susceptibility haplotypes i.e. P2-S2-X1 and P1-S2-X1 have been discovered in ApoAI-CIII-AIV gene cluster on chromosome 11q23, which confer approximately threefold higher risk of coronary heart disease in normal
as well as in the patients having non-insulin diabetes mellitus.
Role in other diseases
A G/A
polymorphism in the
promoter of the ''APOA1'' gene has been associated with the age at which
Alzheimer disease is presented. Protection from Alzheimer's disease by apo-AI may rely on a synergistic interaction with
alpha-tocopherol.
Amyloid deposited in the knee following surgery consists largely of apo-AI secreted from
chondrocytes
Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...
(
cartilage
Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...
cells). A wide variety of
amyloidosis
Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight ...
symptoms are associated with rare ''APOA1'' mutants.
Apo-AI binds to
lipopolysaccharide
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...
or
endotoxin, and has a major role in the anti-endotoxin function of HDL.
In one study, a decrease in Apo-AI levels was detected in
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
patients'
CSF, brain and peripheral tissues.
Epistatic impact of apo A1
Apolipoprotein A1 and APOE interact epistatically to modulate triglyceride levels in coronary heart disease patients. Individually, neither apo A1 nor apo E was found to be associated with triglyceride (TG) levels, but pairwise epistasis (additive x additive model) explored their significant synergistic contributions with raised TG levels (P<0.01).
Factors affecting apo A1 activity
Apo-A1 production is decreased by
calcitriol, and increased by a drug that antagonizes it.
Exercise or
statin treatment may cause an increase in HDL-C levels by inducing apo A1 production, but this depends on the G/A promoter polymorphism.
Interactions
Apolipoprotein A1 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
ABCA1
ATP-binding cassette transporter ABCA1 (member 1 of human transporter sub-family ABCA), also known as the ''cholesterol efflux regulatory protein'' (CERP) is a protein which in humans is encoded by the ''ABCA1'' gene. This transporter is a major ...
*
GPLD1
Phosphatidylinositol-glycan-specific phospholipase D is an enzyme that in humans is encoded by the ''GPLD1'' gene.
Many proteins are tethered to the extracellular face of eukaryotic plasma membranes by a glycosylphosphatidylinositol (GPI) anchor. ...
*
PLTP
Phospholipid transfer protein is a protein that in humans is encoded by the ''PLTP'' gene.
Function
The protein encoded by this gene is one of at least two lipid transfer proteins found in human plasma. The encoded protein transfers phospholip ...
Potential binding partners
Apolipoprotein A1 binding precursor, a relative of APOA-1 abbreviated
APOA1BP
Apolipoprotein A-I-binding protein also known as APOA1BP is a protein that in humans is encoded by the ''APOA1BP'' gene.
Function
APOA1BP binds to APOA1, APOA2, and high-density lipoprotein
High-density lipoprotein (HDL) is one of the five m ...
, has a predicted biochemical interaction with
Carbohydrate Kinase Domain Containing Protein. The relationship between these two proteins is substantiated by
cooccurance across genomes and
coexpression.
The ortholog of CARKD in ''E. coli'' contains a domain not present in any eukaryotic ortholog. This domain has a high sequence identity to APOA1BP. CARKD is a protein of unknown function, and the biochemical basis for this interaction is unknown.
Interactive pathway map
See also
*
Apolipoprotein B
Apolipoprotein B (ApoB) is a protein that in humans is encoded by the gene.
Function
Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, Lp(a), IDL, and LDL particles (LDL—commonly known as "bad cholesterol" when in refer ...
*
Cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
*
ApoA-1 Milano
Apolipoprotein A-1 Milano (also ETC-216, now MDCO-216) is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with ...
References
External links
*
Applied Research on Apolipoprotein-A1*
*
*
{{Lipoproteins
Apolipoproteins
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